FAT10 induces immune suppression by upregulating PD-L1 expression in hepatocellular carcinoma.

The upregulation of programmed death ligand 1 (PD-L1) plays a crucial role in facilitating cancer cells to evade immune surveillance through immunosuppression. However, the precise regulatory mechanisms of PD-L1 in hepatocellular carcinoma (HCC) remain undefined. The correlation between PD-L1 and ubiquitin-like molecules (UBLs) was studied using sequencing data from 20 HCC patients in our center, combined with TCGA data. Specifically, the association between FAT10 and PD-L1 was further validated at both the protein and mRNA levels in HCC tissues from our center. Subsequently, the effect of FAT10 on tumor progression and immune suppression was examined through both in vivo and in vitro experiments. Utilizing sequencing data, qPCR, and Western blotting assays, we confirmed that FAT10 was highly expressed in HCC tissues and positively correlated with PD-L1 expression. Additionally, in vitro experiments demonstrated that the overexpression of FAT10 fostered the proliferation, migration, and invasion of HCC cells. Furthermore, the overexpression of FAT10 in HCC cells led to an increase in PD-L1 expression, resulting in the inhibition of T cell proliferation and the enhancement of HCC cell resistance to T cell-mediated cytotoxicity. Moreover, in vivo experiments utilizing the C57BL/6 mouse model revealed that overexpression of FAT10 effectively suppressed the infiltration of CD8 + GZMB + and CD8 + Ki67 + T cells, as well as reduced serum levels of TNF-α and IFN-γ. Mechanistically, we further identified that FAT10 upregulates PD-L1 expression via activating the PI3K/AKT/mTOR pathway, but not in a ubiquitin-like modification. In conclusion, our findings indicate that FAT10 promotes immune evasion of HCC via upregulating PD-L1 expression, suggesting its potential as a novel target to enhance the efficiency of immunotherapy in HCC.

Response of upper tropospheric water vapor to global warming and ENSO.

The upper tropospheric water vapor is a key component of Earth's climate. Understanding variations in upper tropospheric water vapor and identifying its influencing factors is crucial for enhancing our comprehension of global climate change. While many studies have shown the impact of El Niño-Southern Oscillation (ENSO) and global warming on water vapor, how they affect the upper tropospheric water vapor remains unclear. Long-term, high-precision ERA5 specific humidity data from the European Centre for Medium-Range Weather Forecasts (ECMWF) provided the data foundation for this study. On this basis, we successfully obtained the patterns of global warming (Independent Component 1, IC1) and ENSO (Independent Component 2, IC2) by employing the strategy of independent component analysis (ICA) combined with non-parametric optimal dimension selection to investigate the upper tropospheric water vapor variations and responses to ENSO and global warming. The results indicate that global warming and ENSO are the primary factors contributing to water vapor variations in the upper troposphere, achieving the significant correlations of 0.87 and 0.61 with water vapor anomalies respectively. Together, they account for 86% of the global interannual variations in water vapor. Consistent with previous studies, our findings also find positive anomalies in upper tropospheric water vapor during El Niño years and negative anomalies during La Niña years. Moreover, the influence extent of ENSO on upper tropospheric water vapor varies with the changing seasons.

CircNUP54 promotes hepatocellular carcinoma progression via facilitating HuR cytoplasmic export and stabilizing BIRC3 mRNA.

Circular RNAs (circRNAs) have been implicated in tumorigenesis and progression of various cancers. However, the underlying mechanisms of circRNAs in hepatocellular carcinoma (HCC) have not been fully elucidated. Herein, a new oncogenic circRNA, hsa_circ_0070039 (circNUP54), was identified to be significantly upregulated in HCC through circRNA sequencing. As verified in 68 HCC samples, circNUP54 overexpression was correlated with aggressive cancerous behaviors and poor outcomes. Moreover, the function experiments showed that knockdown of circNUP54 inhibited the malignant progression of HCC in vitro and in vivo, whereas overexpression of circNUP54 had the opposite role. Mechanistic investigations carried out by RNA pull-down, RNA immunoprecipitation, and immunofluorescence revealed that circNUP54 interacted with the RNA-binding protein Hu-antigen R (HuR) and promoted its cytoplasmic export. The cytoplasmic accumulation of HuR stabilized the downstream BIRC3 mRNA through its binding to the 3' UTR region. Consequently, the encoded protein of BIRC3, cellular inhibitor of apoptosis 2 (cIAP2), proceeded to activate the NF-κB signal pathway and ultimately contributed to HCC progression. In addition, depletion of BIRC3 rescued the pro-tumorigenic effect of circNUP54 on HCC cells. Overall, this study demonstrated that circNUP54 facilitates HCC progression via regulating the HuR/BIRC3/NF-κB axis, which may serve as a promising therapeutic target for HCC treatment.

The Synergistic Effect on the Mimetic Optical Structure of Feline Eyes toward Household Health Monitoring of Acute and Chronic Diseases.

A breakthrough in the performance of bionic optical structures will only be achieved if we can obtain an in-depth understanding of the synergy mechanisms operating in natural optical structures and find ways to imitate them. In this work, inspired by feline eyes, an optical substrate that takes advantage of a synergistic effect that occurs between resonant and reflective structures was designed. The synergistic effect between the reflective and resonant components leads to a Raman enhancement factor (EF) of 1.16 × 107, which is much greater than that achieved using the reflective/resonant cavities on their own. Finite-difference time-domain (FDTD) simulations and experimental results together confirm that the mechanism of this synergistic effect is achieved by realizing multiple reflections and repeated absorptions of light, generating a strong local electric field. Thus, a 2-3 order of magnitude increase in sensitivity could be achieved. More importantly, with the homemade centrifugal device, above optical substrates were further used to develop a rapidly highly sensitive household health monitoring system (detection time <3 min). It can thus be used to give early warning of acute diseases with high risk (e.g., acute myocardial infarction (AMI) and cerebral peduncle). Due to the good reusability and storability (9% and 8% reduction in EF after washing 30 times and 9 months of storage, respectively) of the substrates, the substrates thus reduce detection costs (to ∼$1), making them much cheaper to use than the current gold-standard methods (e.g., ∼$16 for gout detection).

Effects of temperature and nitrogen sources on physiological performance of the coccolithophore Emiliania huxleyi.

Both temperature and nutrient levels are rising in worldwide ocean ecosystems, and they strongly influence biological responses of phytoplankton. However, few studies have addressed the interactive effects of temperature and nitrogen sources on physiological performance of the coccolithophore Emiliania huxleyi. In this study, we evaluated algal growth, photosynthesis and respiration, elemental composition, enzyme activity, and calcification under a matrix of two temperatures gradients (ambient temperature 20 °C and high temperature 24 °C) and two nitrogen sources (nitrate (NO3-) and ammonium (NH4+)). When the algae was cultured with NO3- medium, high temperature reduced algal photosynthesis and nitrate reductase activity, but it did not change other indicators significantly relative to ambient temperature. In addition, E. huxleyi preferred NO3- as the growth medium, whereas NH4+ had negative effects on physiological parameters. In the NH4+ medium, the growth rate, photosynthesis and photosynthetic rate, nitrate reductase activity, and particulate organic carbon and particulate organic nitrogen production rate of the algae decreased as temperature increased. Conversely, high temperature increased cellular particulate organic carbon, cellular particulate organic nitrogen, and particulate inorganic carbon levels. In summary, our findings indicate that the distribution and abundance of microalgae could be greatly affected under warming ocean temperature and different nutrient conditions.

A novel risk score system based on immune subtypes for identifying optimal mRNA vaccination population in hepatocellular carcinoma.

PURPOSE: Although mRNA vaccines have shown certain clinical benefits in multiple malignancies, their therapeutic efficacies against hepatocellular carcinoma (HCC) remains uncertain. This study focused on establishing a novel risk score system based on immune subtypes so as to identify optimal HCC mRNA vaccination population. METHODS: GEPIA, cBioPortal and TIMER databases were utilized to identify candidate genes for mRNA vaccination in HCC. Subsequently, immune subtypes were constructed based on the candidate genes. According to the differential expressed genes among various immune subtypes, a risk score system was established using machine learning algorithm. Besides, multi-color immunofluorescence of tumor tissues from 72 HCC patients were applied to validate the feasibility and efficiency of the risk score system. RESULTS: Twelve overexpressed and mutated genes associated with poor survival and APCs infiltration were identified as potential candidate targets for mRNA vaccination. Three immune subtypes (e.g. IS1, IS2 and IS3) with distinct clinicopathological and molecular profiles were constructed according to the 12 candidate genes. Based on the immune subtype, a risk score system was developed, and according to the risk score from low to high, HCC patients were classified into four subgroups on average (e.g. RS1, RS2, RS3 and RS4). RS4 mainly overlapped with IS3, RS1 with IS2, and RS2+RS3 with IS1. ROC analysis also suggested the significant capacity of the risk score to distinguish between the three immune subtypes. Higher risk score exhibited robustly predictive ability for worse survival, which was further independently proved by multi-color immunofluorescence of HCC samples. Notably, RS4 tumors exhibited an increased immunosuppressive phenotype, higher expression of the twelve potential candidate targets and increased genome altered fraction, and therefore might benefit more from vaccination. CONCLUSIONS: This novel risk score system based on immune subtypes enabled the identification of RS4 tumor that, due to its highly immunosuppressive microenvironment, may benefit from HCC mRNA vaccination.

Identification of FOXP1 as a favorable prognostic biomarker and tumor suppressor in intrahepatic cholangiocarcinoma.

BACKGROUND: Forkhead-box protein P1 (FOXP1) has been proposed to have both oncogenic and tumor-suppressive properties, depending on tumor heterogeneity. However, the role of FOXP1 in intrahepatic cholangiocarcinoma (ICC) has not been previously reported. METHODS: Immunohistochemistry was performed to detect FOXP1 expression in ICC and normal liver tissues. The relationship between FOXP1 levels and the clinicopathological characteristics of patients with ICC was evaluated. Finally, in vitro and in vivo experiments were conducted to examine the regulatory role of FOXP1 in ICC cells. RESULTS: FOXP1 was significantly downregulated in the ICC compared to their peritumoral tissues (p < 0.01). The positive rates of FOXP1 were significantly lower in patients with poor differentiation, lymph node metastasis, invasion into surrounding organs, and advanced stages (p < 0.05). Notably, patients with FOXP1 positivity had better outcomes (overall survival) than those with FOXP1 negativity (p < 0.05), as revealed by Kaplan-Meier survival analysis. Moreover, Cox multivariate analysis showed that negative FOXP1 expression, advanced TNM stages, invasion, and lymph node metastasis were independent prognostic risk factors in patients with ICC. Lastly, overexpression of FOXP1 inhibited the proliferation, migration, and invasion of ICC cells and promoted apoptosis, whereas knockdown of FOXP1 had the opposite role. CONCLUSION: Our findings suggest that FOXP1 may serve as a novel outcome predictor for ICC as well as a tumor suppressor that may contribute to cancer treatment.

Trends in prevalence and all-cause mortality of metabolic dysfunction-associated fatty liver disease among adults in the past three decades: Results from the NHANES study.

BACKGROUND: Given the escalating epidemic of obesity and diabetes coupled with redefined diagnostic criteria, it is critical to identify the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD). We sought to determine the prevalence and mortality outcomes of MAFLD subtypes based on diagnostic criteria in the USA over the past three decades. METHODS: Eleven cycles of the National Health and Nutrition Examination Surveys (NHANES; 1988-1994 and 1999-2020) were used, and 72,224 participants were included. MAFLD was defined according to the 2020 International Expert Consensus. Based on diagnostic criteria and risk factors, MAFLD was categorized into seven subtypes: type 1 (obesity subtype), 2 (metabolic unhealthy subtype), 3 (diabetes subtype), 4 (metabolic unhealthy non-diabetes subtype), 5 (obesity and diabetes subtype), 6 (metabolic unhealthy non-obesity subtype), and 7 (mixed subtype). RESULTS: Over the study period, the estimated prevalence of MAFLD increased significantly from 22% in 1988-1994 to 36% in 2017-2020. The prevalence of Type 4 was the highest, followed by that of Type 7, whereas other types were low and almost unchanged over time. Individuals with MAFLD had 19% and 38% increased mortality risks from all causes and cardiovascular disease, respectively. Among them, the metabolically unhealthy participants with normal weight demonstrated a 116% higher risk for all-cause mortality [hazard ratio (HR): 2.16, 95% CI: 1.52-3.08] and a 222% higher risk for cardiovascular mortality (HR: 3.22, 95% CI: 1.72-6.04). Interestingly, stratification and interaction analyses demonstrated a significant impact of metabolic parameters on the relationship between MAFLD and all-cause mortality. CONCLUSIONS: In conclusion, our study identified an increase in MAFLD prevalence and a significant association between metabolic derangements in MAFLD and all-cause or cardiovascular mortality.

Identification of a Novel Ferroptosis-Related Gene Signature for Predicting Prognosis and Responsiveness to Immunotherapy in Hepatocellular Carcinoma.

Purpose: Ferroptosis has been reported to regulate multiple biological behaviors. However, the prognostic and oncologic values of ferroptosis-related genes (FRGs) have not been comprehensively elucidated in hepatocellular carcinoma (HCC). Here, we aimed to construct FRGs-associated signature for stratification of the prognosis of HCC patients. Methods: A list of FRGs was generated from FerrDb. Public databases were used to extract expression matrices and clinical information. TCGA cohort was randomly divided into a training set and a validation set. Prognostic signature for Overall Survival (OS) was established in training set and validated in internal cohorts (TCGA validation set and entire set) and external cohort (ICGC cohort). Additionally, the role of signature in HCC was well investigated by analysis of mutations, gene set enrichment analysis (GSEA), analysis of immune infiltrates, and analysis of response to immune checkpoint blockade (ICB) treatment. The oncogenic effects of ZFP69B on HCC were also investigated in vitro. Results: We identified 12 FRGs-based signature for OS with LASSO regression. Patients were partitioned into different risk groups based on the signature. Overall, patients in different groups had different prognosis. The signature independently predicted OS in multivariate Cox regression analyses. Anti-tumor immune cells including activated CD8 T cells, cytolytic activity, and Th1 cells were negatively correlated with risk score in both TCGC and ICGC cohorts. Furthermore, low-risk patients responded better to ICB than high-risk patients. In addition, knockdown of ZFP69B reduced proliferation, migration, and invasion, and promoted erastin-induced ferroptosis of HCC cells. Conclusion: We developed a prognostic signature based on FRGs to predict OS of HCC patients. And the signature may facilitate clinicians in identifying those who are likely to benefit from ICIs. The results also indicated that ZFP69B might regulate the process of ferroptosis and could be used as a novel potential target for HCC.

Hyperandrogen-induced polyol pathway flux increase affects ovarian function in polycystic ovary syndrome via excessive oxidative stress.

AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in the women of childbearing age. It is characterized by hyperandrogenism and abnormal follicular growth and ovulation. The polyol pathway is a glucose metabolism bypass pathway initiated by aldose reductase (ADR). Androgen induces the expression of ADR in the male reproductive tract, which has a general physiological significance for male reproductive function. Here we investigate whether hyperandrogenemia in PCOS leads to increased flux of the polyol pathway in ovarian tissue, which in turn affects follicular maturation and ovulation through oxidative stress. MAIN METHODS: We used clinical epidemiological methods to collect serum and granulosa cells from clinical subjects for a clinical case-control study. At the same time, cell biology and molecular biology techniques were used to conduct animal and cell experiments to further explore the mechanism of hyperandrogen-induced ovarian polyol pathway hyperactivity and damage to ovarian function. KEY FINDINGS: Here, we find that hyperandrogenism of PCOS can induce the expression of ovarian aldose reductase, which leads to the increase of the polyol pathway flux, and affects ovarian function through excessive oxidative stress. SIGNIFICANCE: Our research has enriched the pathological mechanism of PCOS and may provide a new clue for the clinical treatment of PCOS.

Ocean acidification stimulation of phytoplankton growth depends on the extent of departure from the optimal growth temperature.

Ocean acidification and warming are two major environmental stressors; however, the generality of how warming will alter growth responses of phytoplankton to ocean acidification is less known. Here, enhancement of growth by high CO2 (HC) in Phaeodactylum tricornutum and Thalassiosira weissflogii was most prominent at optimum temperature. The extent to which growth rates in HC cultures were raised compared to low CO2 (LC) cultures tended to decrease with increasing or decreasing temperature, compared to the optimum. Further mechanistic studies in P. tricornutum revealed that cellular carbon and nitrogen content, superoxide dismutase activity, and respiration were generally higher in HC than those in LC at high and low temperatures, whereas PSII photochemical parameters were generally lower in HC than in LC at high and low temperatures. These results indicate that HC-grown cells needed to invest more energy and materials to maintain intracellular homeostasis and repair damage induced by the unsuitable temperatures.

Release of antidiabetic peptides from Stichopus japonicas by simulated gastrointestinal digestion.

Sea cucumber (Stichopus japonicus) is a high-protein food with the potential to release certain peptides through enzymolysis. This work is to explore the characteristics of peptides released from Stichopus japonicus protein in the process of digestion. Hydrolysates were obtained by gastrointestinal digestion and fractioned to <3, 3-10, 10-30 and >30 kDa fractions. Fifty-eight peptides from <3 kDa fraction were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Hydrolysates could improve glucose uptake of 3 T3-L1 cells and high insulin-induced insulin-resistant Hep G2 cells. Molecular docking showed that the released peptides had similar binding mode with anagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor. The <3 kDa fraction in gastro and intestinal digestion showed the greatest DPP-IV inhibitory potency (IC50 0.51 and 0.52 mg/mL, respectively). The results indicated that sea cucumber could be used as a functional food to release antidiabetic peptides through gastrointestinal digestion.

Simultaneous Refinement of Primary Si and Modification of Eutectic Si in A390 Alloy Assisting by Sr-Modifier and Serpentine Pouring Channel Process.

In this study, A390 alloy was prepared using the combined process of a water-cooled copper serpentine pouring channel (SPC) and strontium (Sr) modifier, in order to simultaneously refine primary silicon (Si) and modify eutectic silicon (Si). The nucleation and growth mechanisms of the Si phase were discussed by morphology analysis and non-isothermal analytical kinetics. The results indicate that the size of primary Si is refined to 25.2-28.5 µm and the morphology of eutectic Si is modified from acicular into fibrous. The serpentine pouring channel process stimulates primary Si nucleation due to chilling effect and has no influence on eutectic Si nucleation. Impacts of Sr-modifier on primary and eutectic Si are similar, including three aspects: (1) poisoning of the nucleation site; (2) decreasing the interface energy between Si phase and liquid; (3) raising the activation energy for diffusion across solid-liquid interface. The content of Sr determines which one of the three aspects mentioned above is the dominant factor to promote or restrain the nucleation and growth of the primary and eutectic Si in hypereutectic Al-Si alloy.

Combining Review Text Content and Reviewer-Item Rating Matrix to Predict Review Rating.

E-commerce develops rapidly. Learning and taking good advantage of the myriad reviews from online customers has become crucial to the success in this game, which calls for increasingly more accuracy in sentiment classification of these reviews. Therefore the finer-grained review rating prediction is preferred over the rough binary sentiment classification. There are mainly two types of method in current review rating prediction. One includes methods based on review text content which focus almost exclusively on textual content and seldom relate to those reviewers and items remarked in other relevant reviews. The other one contains methods based on collaborative filtering which extract information from previous records in the reviewer-item rating matrix, however, ignoring review textual content. Here we proposed a framework for review rating prediction which shows the effective combination of the two. Then we further proposed three specific methods under this framework. Experiments on two movie review datasets demonstrate that our review rating prediction framework has better performance than those previous methods.

A Fuzzy Computing Model for Identifying Polarity of Chinese Sentiment Words.

With the spurt of online user-generated contents on web, sentiment analysis has become a very active research issue in data mining and natural language processing. As the most important indicator of sentiment, sentiment words which convey positive and negative polarity are quite instrumental for sentiment analysis. However, most of the existing methods for identifying polarity of sentiment words only consider the positive and negative polarity by the Cantor set, and no attention is paid to the fuzziness of the polarity intensity of sentiment words. In order to improve the performance, we propose a fuzzy computing model to identify the polarity of Chinese sentiment words in this paper. There are three major contributions in this paper. Firstly, we propose a method to compute polarity intensity of sentiment morphemes and sentiment words. Secondly, we construct a fuzzy sentiment classifier and propose two different methods to compute the parameter of the fuzzy classifier. Thirdly, we conduct extensive experiments on four sentiment words datasets and three review datasets, and the experimental results indicate that our model performs better than the state-of-the-art methods.